Hundreds of thousands of anterior cruciate ligaments (ACL) are torn every year and this trend has been increasing with the rise of participation in sports in the general population and in particular in females and older participants. For young and/or athletic active individuals the standard care is based on ligament reconstruction. Several replacement tissues can be envisaged using either grafts (auto, allo and xeno) or artificial materials. Xenografts, ligaments from other animals, and allografts from cadaveric human tissue are possibilities that overcome the need to autologous tissues and avoid the risk of donor-site morbidity. However, their use poses several issues including risks of disease transmission, graft rejection and inflammation. Moreover, in the case of allografts, the supply is so small that the market demand can never be met from this source. Autograft tissues extracted from the patellar tendon, quadriceps tendon-patellar bone or the hamstring tendons are currently the most common sources of grafts for ACL reconstruction. Yet this therapy relies on the extraction of healthy tissue which implies risks of donor-site morbidity, an initial low strength, a high probability of rupture at the initial stages and a long and painful recovery period. The use of artificial prosthetic ligaments as an alternative to autografts could bring substantial improvements in the existing reconstruction therapies.
Several prosthetic devices for ACL replacement have been made over the past thirty years using a wide range of materials. The materials which have been considered for these devices including polyester (Stryker Dacron® ligament prosthesis, Leeds-Keio), polytetrafluoroethylene and fluoropolymers (Gore-Tex®), carbon fibers, polyethylene, nylon and polystyrene. However none of these artificial ligaments have demonstrated positive long term results in vivo. Failures of previous devices mostly originate from mechanical failures or from a lack of biocompatibility. Mechanical failures include i) rupture caused by wear, fatigue or severe loading in the knee and ii) laxity in the joint after creep of the prosthetic ligament or loosening of the fixation element in the bone. Biocompatibility issues primarily manifest as immunogenic particulation leading to chronic synovitis. Due to high incidence of such problems, most if not all the previous artificial ligaments have been withdrawn from the commercial market. For example, no such devices are currently approved for clinical use by the Food and Drug Administration of the United States of America (FDA).
Over the last decades, statistics have been collected that confirm the poor long term efficacy of existing artificial ligaments. A study of 855 artificial cruciate ligaments over a 15-year period found that there was 40-78% failure rate (Fu F. H. et al. American Journal of Sports Medicine, 2000, 28(1), 124-130). Another report found that around 80% of knees which had been reconstructed using Dacron prosthetic ligaments had developed significant osteoarthritic symptoms at a 9 year follow up (Fu F. H. cited above). Similarly, a study of 268 patients revealed that Gore-Tex® anterior cruciate ligament prosthesis yielded a failure rate of 42% with case of effusions, rupture and strong loosening (George M. S. et al, American Journal of Sports Medicine, 2006, 34(12), 2026-2037). Overall, complication rates for artificial ligament operations are of the order of 40-50%, which is much higher than the rate with autologous and allogenic ligaments.
As an alternative to non-biodegradable artificial ligaments, research efforts are being carried out to develop tissue engineered (TE) ligaments for which a biodegradable scaffold first replaces the native ligament and is progressively replaced by a new reconstructed living tissue. Several systems have recently been designed using silk, collagen or polylactic acid biodegradable fibers (Freeman J. W. et al. Journal of Biomechanics, 2010, doi: 10.1016/j.biomech. 2010.10.043). Nevertheless, the management of cell sourcing as well as the control of scaffold degradation while ensuring proper mechanical properties remain unsolved issues that still need to be addressed before clinical use.
Most of the patents deal with the methods of attachment or fixation design to attach an artificial ligament to the bones of a joint. Recent examples are given below.
FR 2 700 111 relates to an artificial ligament consisting of a fixed section and a moving sleeve which form two separate ligaments of the same or different lengths, joined together so that they can slide relative to one another. The two ligaments can be made from plaited, woven or knitted fibres of the same or different materials, with their ends joined together by a thermo-shrink material or a supple adhesive. The outer ligament can be made with sections of reduced resistance which allow its length to be varied. The ligaments can be made from Dacron® (RTM) or other synthetic fibres, or from natural cellulose fibres which are treated to make them biocompatible.
US 2003/114929 discloses a prosthetic ligament including a cord of thermotropic liquid crystal filaments. Preferably the cord is a string or thin rope made by several strands braided, twisted, or woven together. Strands are, preferably, made of a multi-filament thread.
U.S. Pat. No. 5,800,543 relates to an artificial ligament device comprising a plurality of tows of biocompatible material (for example polyester) secured side-by-side in a flat elongate array by braiding, the tows being looped back at one end of the device to form an eye, the flat lengths adjoining the eye being secured to each other side-by-side by stitching, the tows around the eye being grouped together and whipped, and lashing being applied around a base of the eye.
WO 2009/047767 provides a ligament prosthesis having a first end and a second end, comprising a first load bearing element and a second load bearing element, the first and second load bearing elements differing in one or more mechanical properties and being arranged in the prosthesis in series. The load bearing elements may be made from an alloy and, in order to protect nearby organs and tissues from abrasion from the prosthesis and vice versa, may be contained in a sleeve made from biodegradable polymers such as poliglecaprone, polyglycolic acid, polylactic acid, polydioxanone, or co-polymers of the aforementioned polymers.
WO 2009/113076 provides a ligament prosthesis having an undeployed configuration and a deployed configuration. The prosthesis has a resistance to tension in the undeployed configuration that is less than its resistance to tension in the deployed configuration. In the deployed configuration, the prosthesis is capable of twisting and bending. In one embodiment, the prosthesis has a meshwork of filaments woven, knitted or braided into a slender cylinder. The prosthesis may be used to replace an anterior or posterior cruciate ligament.
WO 98/22046 discloses a “free strand” ligament that is naturally self-convoluted between the two ends of the intra-articular median part.
With the foregoing disadvantages of the prior art in mind, it appears that there is a need for a device which i) is biocompatible on the short and long term, meaning after years of implantation in vivo, ii) reproduces closely the non-linear elastic mechanical behaviour of native ligaments and tendons including the stiffness and the toe-region, iii) ensures ultimate tensile stress (strength) and ultimate tensile strain that are safe with respect to the patient's activity. Polymer hydrogels constitute relevant materials in that respect.
Hydrogels, also called aquagels, are hydrophilic polymer networks that can absorb water and swell without dissolving at least temporarily. Depending on the physico-chemical properties of these networks, levels of water absorption can vary greatly from about 10% to thousand times their dry weight. An important characteristic of hydrogels is that they can possess a water content and a molecular structure very similar to those of living tissues. These features confer them biocompatibility, lubricity, rubbery elasticity and possibly biodegradability, which are of interest for biomedical applications and more particularly tissue replacement. Examples of hydrogel forming polymers that are relevant for biomedical applications are polyvinyl alcohol, polyethylene-glycol, polysaccharides, polylactic acids and their copolymers
U.S. Pat. No. 5,981,826 provides a poly(vinyl alcohol) hydrogel construct having a wide range of mechanical strengths for use as a human tissue replacement. It may be especially useful in surgical and other medical applications as an artificial material for replacing and reconstructing soft tissues in humans and other mammals. Soft tissue body parts which can be replaced or reconstructed by the hydrogel include vascular grafts, heart valves, esophageal tissue, skin, corneal tissue, cartilage, meniscus, and tendon. However, the reported tensile modulus of elasticity for the so-prepared material is less than 1 MPa, which is too low as compared to the ultimate tensile stress of ligaments and tendons, which is greater than 100 MPa.
WO/2006/102756 relates to a hydrogel exhibiting anisotropic properties which is poly(vinyl alcohol) produced by preparing a solution of poly(vinyl alcohol) with a pre-selected concentration, thermally cycling the solution by freezing and thawing, stretching the hydrogel and thermally cycling the hydrogel at least one more time. Said anisotropic hydrogel is used for soft tissue replacement selected from vascular vessels, coronary arteries, heart valve leaflets, heart valve stent, cartilage, ligaments and skin. However, the ultimate tensile stress for the so-prepared materials do not exceed 0.4 MPa, which is too low as compared to the ultimate tensile stress of ligaments and tendons, estimated in the range 30-50 MPa.
WO/2001/017574 discloses a hydrogel intended for orthopedic applications wherein the tissue is selected from the group consisting of bone, cartilage, meniscus, bursa, synovial membranes, tendons, ligaments, muscle and vertebral disks. Like for WO/2006/102756, the ultimate tensile stress for the preferred material is about 8 MPa, which is too low for the replacement of most ligaments and tendons.
JP4141178 discloses an artificial tendon and an artificial ligament consisting of polyvinyl alcohol fiber with a tensile strength of 12 g/d or larger and a tensile breaking elongation of 6% or smaller which is much less than the devices of the present invention
A non-biodegradable device that can be installed in-vivo to repair a ligament or tendon, that is biocompatible and that reproduces closely the mechanical properties of native ligaments and tendons as well as ensures the appropriate values of tensile strength and ultimate tensile strain required for ligament or tendon replacement is needed.